Obesity is a major public health concern afflicting 300 million people worldwide. Serious and common complications from obesity include hypertension, diabetes, cardiovascular disease, dyslipidernia, osteoartbritis, sleep apnea, etc. Standard treatments include diet, exercise, behavioral therapy, and medications. Most patients do not succeed at maintaining normal weight. In some with disabling and life-threatening obesity, gastric surgery provides a last resort, despite invasiveness, potential for serious complications, and cost. More effective and novel approaches to the treatment of obesity are needed. One largely untapped focus is the brain itself.
In animal studies, stimulation of the vagus nerve in the abdomen of healthy male rabbits, by electrical pacing during a month, reduces food intake and body mass. Sobocki. J., et al., Microchip vagal pacing reduces food intake and body mass. Hepatogastroenterology 48:1783-1787 (2001). Stimulation of the human vagus nerve to treat eating disorders also has been described. See, for instance, U.S. Pat. No. 6,609,025 (“the '025 patent”) to Barrett et al., assigned to Cyberonics, Inc., and patents discussed therein.
U.S. Pat. No. 5,263,480 to J. Wernicke et al. [“the '480 patent,” which issued on application Ser. No. 07/926,915, filed Aug. 7, 1992, which was a continuation of application Ser. No. 07/649,618 of the same inventors filed Feb. 1, 1991, now U.S. Pat. No. 5,188,104], assigned to the same assignee as [Barrett et al.], discloses treatment for eating disorders including obesity and compulsive overeating disorder by selectively applying modulating electrical signals to the patient's vagus nerve, preferably using an implanted neurostimulator. Modulating signals may be used to stimulate vagal activity to increase the flow of neural impulses up the nerve, or to inhibit vagal activity to block neural impulses from moving up the nerve, toward the brain, for producing excitatory or inhibitory neurotransmitter release.
Barrett et al. in the '025 patent further characterize the teachings of the '480 patent as follows:
Both of these cases of modulating the electrical activity of the vagus nerve have been termed vagus nerve stimulation, or VNS. The '480 patent theorized that VNS could be used for appetite suppression by causing the patient to experience satiety, a sensation of ‘fullness’ of the stomach which would result in decreased food consumption and consequent weight reduction. For example, the stimulus generator of the neurostimulator is implanted in a convenient location in the patient's body, attached to an electrical lead having a nerve electrode implanted on the vagus nerve or branch thereof in the esophageal region slightly above the stomach. If the patient's food consumption over a given period exceeded a predetermined threshold level, detected and measured for example by sensing electrodes implanted at or near the esophagus, the stimulus generator is triggered to apply VNS and thereby normal waking hours except in periods of prescribed mealtimes, or is applied as a result of patient intervention by manual activation of the stimulus generator using external magnet control.
Barrett et al. in the '025 patent also characterize the disclosure of U.S. patent application Ser. No. 09/346,396 (“the '396 application,” filed Jul. 1, 1999 (now U.S. Pat. No. 6,587,719 to Barrett et al., also assigned to Cyberonics, Inc.), as follows:
The aforementioned '396 application discloses a method of treating patients for obesity by bilateral stimulation of the patient's vagus nerve (i.e., bilateral VNS) in which a stimulating electrical signal is applied to one or both branches of the vagus. The parameters of the signal are predetermined to induce weight loss of the patient. The signal is preferably a pulse signal applied at a set duty cycle (i.e., its on and off times) intermittently to both vagi. In any event, VNS is applied at a supra-diaphragmatic position (i.e., above the diaphragm) in the ventral cavity. The electrical pulse stimuli are set at a current magnitude below the retching level of the patient (e.g., not exceeding about 6 milliamperes (mA), to avoid patient nausea) in alternating periods of continuous application and no application. Pulse width is set at or below 500 microseconds (μs), and pulse repetition frequency at about 20-30 Hz. The on/off duty cycle (i.e., first period/second period of the alternating periods) is programmed to a ratio of about 1:1.8. The neurostimulator, which may be a single device or a pair of devices, is implanted and electrically coupled to lead(s) having nerve electrodes implanted on the right and left branches of the vagus.
[i]n dog tests conducted by the applicants herein, the dietary pattern included twice-a-day feedings of approximately 400 grams of solid food with one scoop of soft meat product added to make the food more edible. During the surgical procedure, a threshold referred to herein as the retching threshold was documented while the animal was under anesthesia, based on the threshold value of the stimulus output current of the device at which the animal exhibited a retching or emetic response. The amount of current was adjusted to determine this threshold. Other parameters were left fixed at a frequency of 30 Hertz (Hz), a pulse width of 500 milliseconds (ms), and an on/off cycle of one minute on and 1.8 minutes off.
Barrett et al. in the '025 patent disclose yet another variation of treatment of obesity by vagus nerve stimulation, using bilateral sub-diaphragmatic stimulation, which the '025 patent characterizes as follows:
According to the present invention, a method of treating patients for obesity comprises unilateral or bilateral stimulation of the left and right vagi at a sub-diaphragmatic position (i.e., below the diaphragm) in the ventral cavity, rather than at a supra-diaphragmatic position as taught by the '396 application. The stimulating electrical signal is preferably applied to the vagus two to three inches below the diaphragm, and may be applied either synchronously or asynchronously to both the right and left branches, preferably in the form of a series of pulses applied intermittently to both branches according to a predetermined on/off duty cycle. The intermittent application is preferably chronic, rather than acute. However, continuous application or acute application by bilateral stimulation of the right and left vagi or unilateral contemplated.
The sub-diaphragmatic application of VNS may have an enhanced effect in inducing satiety in the patient, being in closer proximity to the stomach itself. Certainly, in the case of neurostimulator device implantation superficially in the abdominal region of the patient, the sub-diaphragmatic application has an advantage of enabling shorter leads for the nerve electrode(s). Additionally, application of the neurostimulator may be more easily accomplished with this approach as opposed to a supra-diaphragmatic approach which requires accessing the vagi in the chest cavity.
Accordingly, as taught, for instance, by Barrett et al. in the '025 patent, above, implantation of the devices used to provide the electrical pulses to the vagus nerve in abdomen, or supradiaphragmatically or sub-diaphragmatically, typically requires an invasive implantation procedure exposing the patient to risks associated with such invasive procedures. Thus, methods of inducing weight loss in a patient that do not require such invasive surgical implantation procedures are desired.
In addition, none of the patents discussed by Barrett et al. in the '025 patent, nor the '025 patent itself, discloses any clinical results of testing the disclosed methods on human subjects. Greene et al., Perspectives on the metabolic management of epilepsy through dietary reduction of glucose and elevation of ketone bodies, J. Neurochem. 86:529-537 (2003), discloses (at p. 533) that vagal nerve stimulation is a novel therapy that significantly reduces seizure frequency in patients with refractory seizures and asserts that “(the vagus nerve is also known to affect eating behavior and vagal nerve stimulation has been used to treat morbid obesity (Roslin and Kurian 2001)”, where the full citation for the disclosure of “Roslin and Kurian 2001” is given as “Roslin M. and Kurian M. (2001) The use of electrical “Roslin M” is presumably Mitchell S. Roslin, one of the inventors of the '025 patent.
The above cited publication by Roslin and Kurian (Epilepsy Behav. 2, S11-S16, 2001) teaches that
[o]besity is actually defined as having excess adiposity or fat tissue. Since it is more practical to measure height and weight rather than amount of fat, determination of level of obesity is generated using these numbers. The most accurate numerical assessment is obtained by determining the body mass index (BMI). This number is derived by dividing weight in kilograms (or pounds) by height in meters squared (or feet). A BMI of more than 40 is considered morbidly obese. As an example, an individual who is 5 feet 10 inches tall (177.8 cm) and weighs 280 pounds (127 kg) has a body mass index of 40. A patient with a BMI of 25 to 30 is considered overweight; 30 to 35 corresponds to stage I obesity, 35 to 40 to stage II obesity, and >40 to stage III or morbid obesity.
Roslin and Kurian further disclose the basis for their approach toward developing a method of treating obesity using VNS, as follows:
The combination of the anatomic relationship of the vagus nerve to the GI tract and the above physiologic experiments provided the rationale for the investigation of electrical stimulation of the vagus nerve for obesity and development of a preclinical animal experimental program. Despite this appealing theory, one major factor needed to be considered prior to beginning investigation. During the numerous years of clinical experience with vagus nerve stimulation (VNS) for epilepsy, no weight loss was reported, other than a few anecdotal reports. Thus several modifications were necessary. Because we would be best to be in closer proximity to the gastroesophageal junction. Such positioning would avoid stimulation of fibers that join the trunk from the heart and lungs and, we speculated, have a greater likelihood of stimulating our target fibers. Additionally, positioning away from the neck and the recurrent laryngeal nerve would allow the delivery of higher levels of current that could be necessary to stimulate these unmyelinated fibers. Finally, because the right and left trunks have different distributions in the abdomen and the contribution of both could be essential, we chose to investigate bilateral stimulation of the vagus nerve.
Following a preclinical study which Roslin and Kurian considered to study suggest that the use of bilateral VNS is effective in changing eating behavior, with a corresponding weight loss in a canine animal model, the authors describe the initiation of a human “pilot” program, as follows:
The results of the canine study and the known safety of VNS in humans served as the basis for initiating a phase I study. Enrollment began during the summer of 2000, and clinical implantation has started. Thirty patients will be enrolled, all of whom will have their generators activated. To control for placebo, 60% of the patients will have their NCP systems activated 2 weeks after surgery, and those of the other 40% will be activated 14 weeks after surgery. Initial implantation has been performed with an open technique to ensure proper lead placement. Laparoscopic and thoracoscopic techniques will be used in future implants. Because obesity is a chronic disease, long-term data are mandatory before results can be analyzed. Preliminary data may be available late in 2001.
experience with vagus nerve stimulation (VNS) for epilepsy, the disclosure of Roslin and Kurian contemplates a need to stimulate the small unmyelinated C fibers of the nerve and, hence, that VNS stimulation for treating obesity would best be in closer proximity to the gastroesophageal junction, thereby avoiding stimulation of fibers that join the trunk from the heart and lungs and allowing the delivery of higher levels of current that could be necessary to stimulate these unmyelinated fibers. Finally, because the right and left trunks have different distributions in the abdomen and the contribution of both could be essential, these authors chose to investigate bilateral stimulation of the vagus nerve in an animal model and thereafter in human clinical testing.
U.S. Pat. No. 6,611,715 (“the '715 patent”) to Boveja, issued Aug. 26, 2003, discloses apparatus and methods for neuromodulation therapy for obesity and compulsive eating disorders using an implantable lead-receiver and an external stimulator. According to Boveja in the '715 patent:
[a]system and method of neuromodulation adjunct (add-on) therapy for obesity and compulsive eating disorders, comprises an implantable lead-receiver and an external stimulator. Neuromodulation is performed using pulsed electrical stimulation. The external stimulator contains a power source, controlling circuitry, a primary coil, and predetermined programs which control the different levels of therapy. The primary coil of the external stimulator inductively transfers electrical signals to the lead-receiver, which is also in electrical contact with the left vagus nerve. The external stimulator emits electrical pulses to stimulate the vagus nerve according to a predetermined program. In a second mode of operation, an operator may manually override the predetermined sequence of stimulation. The protected. The external stimulator may also be equipped with a telecommunications module to control the predetermined programs remotely.
Further according to Boveja in the '715 patent:
Apparatus and method for neuromodulation, in the current application has several advantages over the prior art implantable pulse generator. The external stimulator described here can be manufactured at a fraction of the cost of an implantable pulse generator. The therapy can be freely applied with [sic, without] consideration of battery depletion. Surgical replacement of pulse generator is avoided. The programming is much simpler, and can be adjusted by the patient within certain limits for patient comfort. And, the implanted hardware is significantly smaller.
U.S. Pat. No. 6,449,512 (“the '512 patent”) to Boveia, issued Sep. 10, 2002, discloses apparatus and methods for treatment of urological disorders using a “programmerless” implantable pulse generator system, which is characterized as follows:
System and method of neuromodulation therapy for urinary incontinence disorders comprises a lead to selectively stimulate the sacral plexus and an implantable pulse generator for providing the appropriate pulses. The implantable pulse generator having prepackaged/predetermined programs stored in the memory of the pulse generator, and means for accessing these with an external magnet. The pulse generator adapted to selectively activate predetermined programs with the external magnet, thereby eliminating the need for an external programmer. The elimination of the external programmer resulting in significant cost reduction with essentially the same functionality.
vagus nerve stimulation, Neurology 59:463-464 (2002) reported on weight loss in patients who underwent VNS implantation for treatment of epilepsy for up to two years, as follows:
Of the 27 patients for who complete data were available, 17 had lost weight. Weight in the remaining patients fluctuated, without a specific pattern toward weight gain.
Eight patients (25%) (four men, age range 18-41) had significant weight loss of more than 5% of body weight, and of these, five lost more than 10% of body weight. Two patients lost more than 5% of the weight in the first 6 months, four at 1 year, and six in 2 year. More than 10% of weight loss was seen in one patient after 6 months, in two patients after 1 year, and in three patients after 2 years of VNS (figure [captioned ““Percentage of weight loss vs months of follow-up for each patient found with this characteristic side effect.”]). In none of our patients was VNS discontinued or the generator removed due to weight loss.
Burneo et al. concluded that,
“[a]lthough weight loss may be multifactorial, its occurrence in our patients undergoing VNS implantation appears causally related. This may be due to decreased appetite, resulting in changes in eating behaviors, or to gastrointestinal side effects, such as dyspepsia, previously reported as a side effect of VNS [citations omitted]. Even though this was not a control-case study, patients and physicians should be aware of weight loss as an associated phenomenon of VNS stimulation.”
Accordingly, the report of Burneo et al. does not disclose whether the patients who lost weight in this epilepsy study were obese or of normal weight and does not teach or suggest should be aware of weight loss as an associated phenomenon [or “characteristic side effect”] of VNS stimulation.”
It is known that, in the human body the innervation of the right and left vagus nerves is different. The innervation of the right vagus nerve is such that stimulating it results in profound bradycardia (slowing of the heart rate). The left vagus nerve has some innervation to the heart, but mostly innervates the visceral organs such as the gastrointestinal tract. It is further known that stimulation of the left vagus nerve does not cause substantial slowing of the heart rate or cause any other significant deleterious side effects.